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PHARMACOKINETICS |
From Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany (Dr Stangier, Dr Nehmiz, Dr Rathgen, H. Stähle); Departments of Orthopaedic Surgery, Sahlgrenska University Hospital/Östra, Göteborg, Sweden (Dr Eriksson); Department of Orthopaedics, Buskerud Central Hospital, Drammen, Norway (Dr Dahl); Orthopedic Department, North Älvsborgs Hospital, Trollhättan, Sweden (Dr Ahnfelt); and Boehringer Ingelheim, Sweden (R. Svärd).
Address for reprints: Joachim Stangier, PhD, Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse, Biberach an der Riss, D-88397, Germany.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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. A decrease in the mean dabigatran AUC0- (904 to 705 ng•h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC0-24 of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
Key Words: Dabigatran etexilate • direct thrombin inhibitor • pharmacokinetics • total hip replacement • venous thromboembolism
Research has therefore focused on the identification of synthetic, low-molecular-weight, oral, active direct thrombin inhibitors. Dabigatran etexilate (BIBR 1048) is the orally active prodrug of dabigatran (BIBR 953 ZW), a specific, competitive, and reversible inhibitor of thrombin.3 Dabigatran is not orally available, and therefore dabigatran etexilate, which is rapidly converted to dabigatran, has been developed. The antithrombotic effect of dabigatran, following both parenteral administration of dabigatran and oral administration of dabigatran etexilate, has been shown to be potent in different animal models of thrombosis.4-6 In healthy volunteers, dabigatran is well tolerated and primarily renally excreted. The absolute bioavailability is 3.5% to 5%. Cytochrome P450 isoenzymes are not involved in the metabolism of dabigatran, and the compound neither induces nor inhibits cytochrome P450 isoenzyme activity. Dabigatran is conjugated to activated glucuronic acid to form an acylglucuronide conjugate.
A recently completed study (BISTRO I) explored the safety and efficacy of oral postoperative administration of dabigatran etexilate in 289 patients undergoing total hip replacement (THR).7 Treatment with dabigatran etexilate tablets at doses from 12.5 to 300 mg twice daily for 6 to 10 days showed an adequate safety profile and a trend for efficacy in this patient population, with the first oral dose being administered 4 to 22 hours postsurgery. Approximately 20% of patients, however, had low plasma concentrations after the first dose, with high interindividual variability in the pharmacokinetic parameters. In view of this high interindividual variability with the trial tablet used, a capsule formulation with an improved pharmacokinetic profile was developed.
Recent studies evaluating various antithrombotic therapies, including low-molecular-weight heparin (LMWH), indirect and direct FXa inhibitors, and low-molecular-weight thrombin inhibitors, suggest that commencement of anticoagulation in close proximity to surgery is essential for an optimal thromboprophylactic effect.8-11 Consequently, the effect of surgery on the absorption of a new capsule formulation, administered early in the postoperative period, required further investigation.
The primary objective of these 2 studies was therefore to investigate the pharmacokinetic profile of the capsule formulation of dabigatran etexilate. This was initially performed in healthy volunteers in fasting and fed states and then in conjunction with a proton pump inhibitor to examine the extent of absorption with alterations in gastric pH. Subsequently, it was evaluated in patients receiving their first dose 1 to 3 hours following THR surgery. Primary endpoints in both studies were the rate and extent of dabigatran etexilate absorption, as assessed by the area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax), and time to peak plasma concentration (tmax).
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Phase I Pharmacokinetic Study in Healthy Volunteers
Subjects
Healthy male volunteers aged between 18 and 55 years, with a body mass index (BMI) between 18.5 and 30 kg/m2, were included in this study.
Study Design
This was a single-dose, 3-way crossover study. Dabigatran etexilate was administered as a 150-mg capsule in the following ways: after an overnight fasting period, with coadministration of pantoprazole (40 mg twice daily, started 2 days before administration of study drug), and following a high-fat, high-caloric breakfast. The crossover sequences for the 3 treatments were equally randomly assigned to 18 subjects. The study was carried out in accordance with the principles of the Declaration of Helsinki and had received independent ethics committee approval. All subjects gave written informed consent prior to the study. Pharmacokinetic parameters were derived from dabigatran plasma concentration-time profiles obtained by serial blood sampling collected predose and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after study drug administration. Blood samples (approximately 2 mL) were collected in EDTA tubes and centrifuged at 4°C for 10 minutes at 4000g. Plasma was divided into 2 aliquots and stored at about -20°C in labeled polypropylene vials until analysis. Quantitative determinations of dabigatran concentrations were performed using a liquid chromatography/tandem mass spectroscopy (LC-MS/MS) method. Initially, 80-µL sample volumes were transferred to autosampler vials. The samples were analyzed by a Sciex API 3000 (PerkinElmer, Boston, Mass) LC-MS/MS system. An electrospray ion source with atmospheric pressure ionization was used for measurements performed in the positive ionization mode. Separation was achieved by direct injection on a precolumn and subsequent transfer by column switching onto the analytical high-performance liquid chromatography column. Monitored ions were 472.2 
289.5 (dabigatran), 478.2 295.6 (internal standard), and 648.2 288.9 (dabigatran glucuronide). The lower limit of quantification (LOQ) was 1.00 ng/mL.
The pharmacokinetic parameters of dabigatran were calculated by noncompartmental analysis of the plasma concentration-time data using WinNonlin, Professional Version 3.2 (Pharsight Corporation, Mountain View, Calif).
On the basis of previous experience, we assumed an intrasubject coefficient of variation for AUC with dabigatran of 
15%. To demonstrate bioequivalence (ie, confidence interval within 0.8-1.25) for the mean treatment ratios (test/reference) between 0.91 and 1.10 with 80% power at a 5% level of significance, a sample size of 18 subjects was required. The sample size was calculated according to Diletti et al.12
Statistical analysis of AUC0- and Cmax was based on an analysis of variance (ANOVA) model using a logarithmic scale. Differences between the expected logarithm of test and reference means were estimated with calculation of the corresponding 2-sided 90% confidence intervals (CIs).13 No interaction was to be concluded if the 90% CI for the treatment ratios fell within the range of 0.80 to 1.25. The software program SAS, Version 8.2 (SAS Institute, Cary, NC), was used for the statistical analysis.
Phase II Pharmacokinetic Study in Patients Undergoing Total Hip Replacement
Patients
In this study (known as BISTRO Ib), consecutive patients were considered for inclusion if they were aged over 18 years, weighed at least 40 kg, and were scheduled to undergo primary elective THR. Patients were excluded if they had a bleeding disorder, including intracranial, intraocular, gastrointestinal, or pulmonary bleeding; known thrombocytopenia or history of hemorrhagic stroke; known renal or liver disease; alcohol or drug misuse; known ongoing or active malignancy; or treatment with another study drug within the past month.
Study Design
This was an uncontrolled, open-label study conducted at 9 sites in Sweden and 3 in Norway. The study was conducted according to the ethical principles stated in the Declaration of Helsinki and applicable regulations. The protocol was approved by independent ethics committees, and written informed consent was obtained from all patients prior to inclusion. A single oral dose of 150 mg dabigatran etexilate was given 1 to 3 hours postsurgery. This time window of 1 to 3 hours following surgery was chosen on the basis that early exposure to dabigatran etexilate would most effectively prevent thrombus generation. All concomitant treatments prescribed and administered at the discretion of the investigator were acceptable and recorded. In accordance with the local routine practice for prophylaxis against deep-vein thrombosis (DVT), all patients received a dose of enoxaparin, 40 mg subcutaneously, in the evening or early morning prior to surgery. Following administration of dabigatran etexilate, thromboprophylaxis was then continued at the investigator's discretion, with subsequent doses not being administered until at least 10 hours following the dabigatran etexilate dose.
Monitoring of patient safety—including serious adverse events during the hospital stay, especially any signs and symptoms of clinical DVT, pulmonary embolism (PE), or bleeding episodes—was performed throughout the study.
Pharmacokinetic assessments. Blood was drawn prior to the single 150-mg dose of dabigatran etexilate and then 1, 2, 4, 6 to 8, 10 to 18, and 24 hours post-dosing. Blood samples were collected through a venous catheter placed during the operation, and after discarding the first few milliliters of blood, samples were collected in syringes and put on ice before processing. Blood samples were centrifuged at 4°C for 10 minutes at 4000g and stored at -20°C for the determination of plasma concentrations of dabigatran using a validated LC-MS/MS method described previously. A profile of plasma concentration versus time for dabigatran following drug administration was obtained for each patient who had taken the single dose. From the plasma concentration-time curves, the extent of absorption of dabigatran over 24 hours (AUC0-24) was determined. The AUC was calculated by the linear trapezoidal method up to the time point of the last measurable concentration. Cmax and tmax were also determined.
Prior to trial initiation, 4 pharmacokinetic acceptance criteria for future trial use were defined with respect to drug exposure following administration of the capsule formulation in the postoperative period:
The latter criterion was set at 30% because it was assumed that, independent of drug formulation, factors including anesthesia, gastrointestinal paresis, and other surgical effects would cause absorption delays in some patients.
Statistical analyses. Drug plasma levels and pharmacokinetic parameters were analyzed descriptively in this uncontrolled trial. The theoretical proportion of patients with low drug absorption (AUC <50% of the steady-state AUC with the 150-mg tablet in BISTRO I) and its exact 95% CI were determined. For a secondary analysis, a logistic regression model was developed to evaluate the dependence of low absorption on various covariates. For all dichotomous covariates, the reference value for the computation of the odds ratio was the absence of the covariate. Therefore, an odds ratio greater than 1 means an increase of the odds for low absorption or, more generally, for low exposure, if the covariate is present. As for the healthy volunteer trial, the software program SAS, Version 8.2 (SAS Institute, Cary, NC), was used for the statistical analysis.
Determination of sample size. The sample size was determined by consideration of the CI for the percentage of patients with low absorption; based on an assumed percentage of 10%, the CI was sufficiently narrow to exclude a 20% proportion if 45 patients could be evaluated. The number of patients was increased to 60 to account for the possibility of nonevaluable patients.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Coadministration of food resulted in a delay in absorption of dabigatran etexilate, with the median tmax increasing from 2.0 to 4.0 hours. Mean AUC0- (904 ng•h/mL [fasted] and 895 ng•h/mL [fed]) and mean Cmax (111 ng/mL [fasted] and 106 ng/mL [fed]) were essentially unchanged in the fasted state compared with fed conditions. The geometric mean of the individual ratios of AUC0- for dabigatran with food to that without was 1.08 (CI = 0.89-1.31), and for Cmax, the ratio was 1.02 (CI = 0.83-1.27). Interindividual variability of AUC0- and Cmax after administration of dabigatran etexilate with food was reduced compared with the fasted state (percent coefficient of variation [CV%] reduced from 44% and 42% to 21% and 24%, respectively).
Pretreatment with pantoprazole resulted in a markedly lower AUC0- and Cmax. The geometric mean values of the individual ratios and 90% CIs for AUC0- and Cmax following pantoprazole to those without pretreatment were 0.68 (CI = 0.53-0.86) and 0.60 (CI = 0.46-0.79), respectively. Interindividual variability was high, with mean CV% between 56% and 64%, respectively. The median tmax was 2 hours for both groups, with the mean terminal half-lives being 8.7 hours for those not receiving pantoprazole compared with 7.8 hours for the group receiving pantoprazole.
Adverse Events
One subject reported a severe headache during treatment with dabigatran etexilate, but this was not thought to be related to administration of the study drug. Four other volunteers reported adverse events during the study, with 3 reporting headache, all classified as mild to moderate in intensity. None of the adverse events was thought related to the study drug, and all subjects fully recovered.
Phase II Pharmacokinetic Study in Total Hip Replacement
A total of 62 patients scheduled for elective primary THR were enrolled in the BISTRO Ib study at 12 centers from April to May 2002. Two patients withdrew their consent prior to surgery and were therefore not eligible for the study or study drug administration. One patient withdrew from the study after surgery and prior to administration of the study drug. Therefore, the population receiving single-dose dabigatran etexilate 150 mg was 59 patients. As there were no relevant protocol deviations, the per protocol population is identical with 59 treated patients.
Patient demographic and surgical characteristics for patients administered dabigatran etexilate are shown in Table I. The median age was 68.0 years (range, 36-90 years), and 47.5% of the patients were female. Osteoarthrosis was the predominant indication for surgery (97% of patients), and the majority of patients (92%) underwent regional anesthesia. The median time between surgery and dabigatran etexilate administration was 100 minutes.
Pharmacokinetic Profile
Following drug administration, immediate onset of absorption was seen in the majority of treated patients, with considerable plasma levels of dabigatran measurable after 1 hour. Two patients showed a delay in absorption of 4 and 6 hours following drug administration. The Cmax of dabigatran occurred between 1 and 24 hours following drug administration, with the mean being 75.8 ng/mL, which occurred at a median tmax of 6 hours (Table III). In 13 patients (22%), tmax exceeded 10 hours. Due to the limited number of sampling time points collected beyond 4 hours following drug administration, it was not possible to determine the actual tmax in a few patients. The mean AUC0-24 was 962 ng•h/mL following the single dose of 150 mg, which is comparable to the AUC0- of 904 ng•h/mL seen in the healthy volunteer study during fasted administration and was approximately 88% of the AUCss observed with repeated administration of the same dose (150-mg tablet once daily) during the BISTRO I study. Interindividual variability was high, with coefficients of variation being greater than 65% for both the Cmax and AUC0-24. A profile of plasma concentration versus time is displayed in Figure 2.
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Drug Absorption
Thirteen of 59 patients (22.0%; 95% CI = 12.3%-34.7%) displayed a low extent of absorption according to the predefined criterion of AUC0-24 being less than 50% of the steady-state AUC of the 150-mg tablet in the BISTRO I trial. Four of these patients had an AUC0-24 of less than 20% (range, 11.7%-17.6%), whereas another 4 patients had an AUC0-24 between 20% and 30% of the AUCss (range, 24.9%-28.4%). Furthermore, 4 patients had an AUC0-24 between 30% and 40% (range, 31.9%-38.1%), with the AUC0-24 of 1 patient being 45.1% of the AUCss. Four patients vomited within 2 hours of drug administration, with 2 of these patients being classified as low absorbers (17.6% and 15.2% of the AUCss).
Covariates of Absorption
Only gender and creatinine clearance (CrCl) had a significant influence on the proportion of patients with low exposure (AUC) to dabigatran (Table IV). Females had a 4-fold lower odds of low exposure (odds ratio = 0.25; 95% CI = 0.05-0.95; P = .04) compared with male patients. Interindividual variability was also greater in female patients, with a trend toward higher plasma concentrations and AUC0-24. The mean AUC0-24 in female and male patients were 1160 and 781 ng•h/mL, respectively.
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The odds ratio for lower AUCs according to any increase in CrCl was computed for 10-mL/min increments. In general, the odds for low exposure were 30% higher if the CrCl increased by 10 mL/min (odds ratio = 1.32; 95% CI = 1.01-1.80; P = .04). A nonsignificant trend was seen for low absorption, with other parameters including increased body mass index, younger age, and decreased time interval between surgery and dabigatran etexilate administration. In view of the frequent administration of opioids to patients in the perioperative period and their ability to slow gastrointestinal motility, the coadministration of opioids was assessed. Onset of absorption was unaffected by the administration of opioids, with considerable plasma levels of dabigatran measurable 1 hour following drug administration. In most patients, a relatively low volume of fluid (<100 mL) was taken together with the capsule, but this did not appear to have any affect on the extent of absorption.
Adverse Events
One patient experienced a severe drop in hemoglobin, which required a blood transfusion, and moderate hypotension, both of which were classified as serious adverse events due to prolonged hospitalization. The events were not related to the study drug by the investigator. There were no deaths during the study. The most common adverse event reported was nausea and vomiting, both considered by the investigator to be related to surgical procedures rather than administration of dabigatran etexilate. Most of these adverse events were reported more than 2 hours following administration of the single dose of dabigatran etexilate. No symptoms of DVT or PE were reported, and no patients were lost to follow-up.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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In the healthy volunteer study, administration of dabigatran etexilate as a capsule with food had no relevant effect on the extent of absorption of dabigatran, although there was reduced interindividual variability of plasma concentrations compared with the fasted state. With coadministration of dabigatran etexilate and pantoprazole, a moderate decrease in the extent of dabigatran absorption was noted. Although there was high interindividual variability in dabigatran plasma concentrations following concomitant administration with pantoprazole, this might be explained by a variable effect of the proton pump inhibitor on gastric acid secretion in healthy volunteers.
In the BISTRO Ib study, the oral capsule formulation of dabigatran etexilate administered to patients 1 to 3 hours following THR surgery showed an acceptable absorption profile. Using criteria for the minimal extent of absorption, the proportion of patients with a low extent of absorption, and time to peak plasma concentrations, the acceptability of drug exposure following postoperative administration of the capsule formulation was evaluated. The time criteria for the absorption of dabigatran etexilate were set at no longer than 6 hours to detectable plasma concentrations of dabigatran, with a peak no later than 10 hours. Both criteria were achieved, with the delay in absorption being less than 6 hours postdose and the median time to peak concentration being 6 hours. Substantial plasma concentrations were seen early following drug administration and well before the tmax of 6 hours. Furthermore, the AUC0-24 of dabigatran was approximately 88% of those seen at steady state using the previous tablet formulation in the BISTRO I study and 106% of the AUC0- in the single-dose, healthy volunteer study. The high mean bioavailability following this single dose, compared with the steady-state AUC, ensures that therapeutic plasma levels will have a high likelihood of being attained.
Postoperative initial administration of antithrombotic therapies has been demonstrated to be an effective method for the prevention of DVT following lower limb orthopedic surgery.14 In some regions, thromboprophylaxis is not commenced until 12 to 24 hours after surgery. In the BISTRO Ib study, absorption of the first postoperative dose of dabigatran etexilate, 1 to 3 hours following surgery, occurred relatively slowly compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations were not reached until 6 hours following administration, or until 7 to 8 hours following surgery. In view of the increased bleeding risk for patients immediately following surgery, this slow and steady absorption profile in the early postoperative period would seem to be an advantageous strategy. Indeed, rapid absorption of a direct thrombin inhibitor with high peak plasma concentrations, which is likely to occur after subcutaneous drug administration, might be associated with an increased risk of bleeding in the perioperative period. It is noted, however, that contributing factors such as anesthesia, gastrointestinal paresis, and surgical effects will mean that a proportion of patients will experience absorption delays independent of the oral drug formulation. Although the BISTRO Ib study did not predict whether impaired absorption persists with subsequent doses, the BISTRO I study demonstrated that slow and delayed absorption is usually only present on the day of surgery,7 and on subsequent days, absorption of dabigatran is rapid, with peak plasma concentrations attained 2 hours after drug administration.
Impaired renal function in the BISTRO Ib study was noted to increase plasma concentrations of dabigatran. This is because a decrease in CrCl will result in slower drug elimination, which in turn increases plasma concentrations and thereby decreases the probability for low drug exposure in such patients. Due to the terminal elimination half-life of approximately 14 hours, it is anticipated that the AUC will increase following repeated twice-daily administration due to the accumulation of dabigatran. The ratio of accumulation will depend on the CrCl, which is an indicator of renal function. In healthy volunteers, a ratio of accumulation of 1.7- to 2.5-fold was observed. Other covariates of absorption examined in the BISTRO Ib study may not necessarily occur independently. Associations between female gender and body mass index may coexist, along with those between age and renal function. Some patients may also receive their first dose of dabigatran etexilate later due to nausea, which may be related to postoperative gastric retention and slow passage into the duodenum. Because patients with known renal and liver dysfunction were excluded from this study, data from future studies will be required to confirm any of these interactions.
In summary, the pharmacokinetic characteristics of this capsule formulation of dabigatran etexilate, administered both to volunteers and then to patients 1 to 3 hours postoperatively, was well tolerated and adequately absorbed in the majority of patients. The pharmacokinetic profile of the capsule formulation justifies early, postoperative oral drug administration in further trials in this population. A recently completed, large dose-finding study (BISTRO II),15 using the same capsule and early dosing regimen, evaluated the effect of dabigatran etexilate on clinical outcomes.
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APPENDIX |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Norway—Regional komite for medisinsk forskningsetikk, Oslo (T. Kristiansen, R. Mjaaseth, E. Mohr).
Sweden—Forskningsetikkommittén Göteborg (L. Ahnfelt, B. Edshage, B. I. Eriksson, A. Folestad, B. Paulsson, J. Sjögren); Forskningetikkommittén Linköping (C. Andersson, L. G. Petersson); Forskningetikkommittén Lund (P. Hansson).
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Norway—Sentralsjukehuset i Hedmark, Elverum (T. Kristiansen); Telemark Sentralsykehus, Skien (R. Mjaaseth); Fylkessykehuset i Haugesund, Haugesund (E. Mohr).
Sweden—Sjukhuset i Falköping, Falköping (L. Ahnfelt); Universitetssjukhuset, Linköping (C. Andersson); Kungälvs sjukhus, Kungälv (B. Edshage); Sahlgrenska Universitetssjukhuset/Östra, Göteborg (B. I. Eriksson); Sahlgrenska Universitetssjukhuset/Mölndal, Mölndal (A. Folestad); Länssjukhuset, Halmstad (P. Hansson); Sjukhuset Lidköping, Lidköping (B. Paulsson); Länssjukhuset i Kalmar, Kalmar (L. G. Petersson); Sjukhuset i Varberg, Varberg (J. Sjögren).
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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1. Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med. 2003;163: 759-768.
2. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl): 204S-33S.
3. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem. 2002;45: 1757-1766.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Stassen JM, Hauel NH, Nar H, Ries UJ, Priepke HWM. Ex vivo anticoagulant activity of BIBR 953 ZW, a novel synthetic direct thrombin inhibitor and of its prodrug BIBR 1048 MS in different animal species [abstract P763]. Thromb Haemost. 2001;86: 216.
5. Wienen W, Nar H, Ries UJ, Priepke HWM, Hauel NH, Stassen JM. Effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS on experimentally-induced clot formation and template bleeding time in rats [abstract P761]. Thromb Haemost. 2001;85: 216.
6. Wienen W, Nar H, Ries UJ, Priepke HWM, Hauel NH, Stassen JM. Antithrombotic effects of the direct thrombin inhibitor BIBR 953 ZW and its orally active prodrug BIBR 1048 MS in a model of venous thrombosis in rabbits [abstract OC853]. Thromb Haemost. 2001;86: 232.
7. Eriksson BI, Dahl OE, Ahnfelt L, et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost. 2004;2: 1573-1580.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med. 2000;160: 2199-2207.
9. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162: 1833-1840.
10. Eriksson BI, Bergqvist D, Kalebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet. 2002;360: 1441-1447.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Lee A, Agnelli G, Büller H, et al. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation. 2001;104: 74-78.
12. Diletti E, Hauschke D, Steinijans VW. Sample size determination for bioequivalence assessment by means of confidence intervals. Int J Clin Pharmacol Ther Toxicol. 1992;30(suppl 1): S51-S58.
13. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15: 657-680.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl): 338S-400S.
15. Eriksson BI, Dahl OE, Buller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3: 103-111.[CrossRef][Web of Science][Medline]
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